Aims Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPC) frequently presents with early cervical lymph node metastasis despite favorable prognosis. The spatial immune mechanisms underlying this paradox remain unclear. We aimed to characterize immune programs within peritumoral lymphoid follicular regions (LFRs) and tumor tissue regions (TTRs) in HPV-positive OPC and explore their association with nodal metastasis. Methodology Formalin-fixed paraffin-embedded specimens from resected palatine tonsil-derived OPC (n=6) were analyzed using the GeoMx Digital Spatial Profiler. Regions of interest were selected in LFRs and TTRs. Differential gene expression, single-sample gene set enrichment analysis (ssGSEA), and immune cell deconvolution (CIBERSORTx) were performed. Eosinophil and mast cell infiltration was assessed by immunohistochemistry. Results HPV-positive LFRs showed enrichment of B-cell survival pathways compared with HPV-negative cases. Among HPV-positive tumors, metastasis-negative cases showed a Th2-skewed immune profile in LFRs with increased naïve B cells, plasma cells, eosinophils, activated mast cells, and M2 macrophages. ssGSEA revealed enrichment of HALLMARK_ESTROGEN_RESPONSE signatures in metastasis-negative LFRs, correlating with eosinophil and mast cell fractions. In contrast, metastasis-positive tumors exhibited inflammatory signaling and bile acid metabolism pathways in LFRs. Immunohistochemistry confirmed compartment-specific accumulation of eosinophils and mast cells in non-metastatic HPV-positive tumors. Conclusion HPV-positive OPC without nodal metastasis displays a spatially organized Th2-biased immune niche within peritumoral lymphoid structures. Metastatic tumors show inflammatory and bile acid metabolic activation. Spatial immune architecture in tumor-associated lymphoid compartments may influence lymphatic dissemination and represent a potential translational target in HPV-associated OPC.